A new cytotoxic
acridine alkaloid that exhibited antitumor activity in vivo was isolated from a marine Dercitus species sponge collected at a depth of 160 m in the Bahamas. This violet
alkaloid, designated
dercitin, inhibited the proliferation of cultured murine and human
leukemia, lung, and colon
tumor cells at nM concentrations (IC50 values of 63-150 nM) and prolonged the life of mice bearing ascitic P388
tumors (%T/C = 170, 5 mg/kg, i.p., QD1-9).
Dercitin was also active against i.p.
B16 melanoma and modestly inhibited the growth of s.c.
Lewis lung carcinoma on the same schedule.
DNA blocked the antiproliferative effects of the agent in culture, and incorporation studies indicated that
dercitin disrupted
DNA and
RNA synthesis with less effects on
protein synthesis, similar to the effects of known
DNA intercalators. After 1-h exposure to 400 nM
dercitin, the rates of incorporation of [3H]
uridine, [3H]
thymidine, and [3H]
leucine by cultured P388 cells were inhibited 83, 61, and 23%, respectively. Equilibrium dialysis indicated that
dercitin bound
calf thymus DNA with an affinity of 3.1 microM and maximal binding of 0.20 mol
dercitin/mol base pair. Binding involved intercalation as evidenced by ability to relax supercoiled phi X174
DNA (half maximal concentration for
dercitin relaxation was 36 nM). The effects of
dercitin on
DNA mobility were reversible, and complete relaxation of
DNA with
topoisomerase I in the presence of
dercitin followed by
phenol extraction resulted in the appearance of
supercoiled DNA.
Dercitin, at microM concentrations, had a small effect in the K+-
sodium dodecyl sulfate assay using cultured P388 cells, suggesting minimal inhibition of topoisomerase activity. But,
dercitin completely inhibited
DNA polymerase I/
DNase nick translation of
DNA at 1 microM. Relaxation of
DNA at a given concentration was greater than inhibition of nick translation suggesting that the effects of
dercitin on
enzyme activity were secondary to changes in DNA conformation. Results indicate that
dercitin is a new marine
natural product that probably exerts its
biological effects through intercalation into
nucleic acids.